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Надходження в арсенали озброєнь фосфорорганічних отруйних речовин (ОР) нервово-паралітичної дії знаменувало апогей розвитку хімічної зброї. У 1939 р. було отримано зарин, а наприкінці 1944 р. — зоман, що належали до нового класу смертельних ОР нервово-паралітичної дії й у багато разів перевершували за своєю токсичністю ОР часів Першої світової війни. Промислове виробництво зарину почалося в 1952 р. В середині 1961 р. у США почали виробляти малолетючу стійку фосфорорганічну ОР під шифром VХ, особливо небезпечну при потраплянні навіть невеликих кількостей її на шкіру. За роки Другої світової війни в США на 17 технологічних установках було вироблено 135 тис. т різних ОР, з яких більше половини припадало на іприт. Останнім було споряджено близько 5 млн снарядів і 1 млн хімічних авіаційних бомб. Результатом робіт у галузі ОР, що впливають на центральну нервову систему людини, стало детальне дослідження до 1962 р. 3-хінуклідинілового ефіру бензилової кислоти, що має шифр ВZ. Вона перебувала на озброєнні американської армії і в експериментальному варіанті застосовувалася у В’єтнамі. У післявоєнні роки в армії США на зміну старих речовин подразнюючої дії були прийняті нові речовини — СS і СR, що стали результатом спільних англо-американських досліджень. За подразнюючою дією речовина CS значно перевершує іританти часів Першої світової війни. У 1993 р. було прийнято Міжнародну конвенцію про заборону хімічної зброї, що набрала чинності 29 квітня 1997 р.

Organophosphate (OP) nerve agents and pesticides are a class of neurotoxic compounds that can cause status epilepticus (SE), and death following acute high-dose exposures. While the standard of care for acute OP intoxication (atropine, oxime, and high-dose benzodiazepine) can prevent mortality, survivors of OP poisoning often experience long-term brain damage and cognitive deficits. Preclinical studies of acute OP intoxication have primarily used rat models to identify candidate medical countermeasures. However, the mouse offers the advantage of readily available knockout strains for mechanistic studies of acute and chronic consequences of OP-induced SE. Therefore, the main objective of this study was to determine whether a mouse model of acute diisopropylfluorophosphate (DFP) intoxication would produce acute and chronic neurotoxicity similar to that observed in rat models and humans following acute OP intoxication. Adult male C57BL/6J mice injected with DFP (9.5 mg/kg, s.c.) followed 1 min later with atropine sulfate (0.1 mg/kg, i.m.) and 2-pralidoxime (25 mg/kg, i.m.) developed behavioral and electrographic signs of SE within minutes that continued for at least 4 h. Acetylcholinesterase inhibition persisted for at least 3 d in the blood and 14 d in the brain of DFP mice relative to vehicle (VEH) controls. Immunohistochemical analyses revealed significant neurodegeneration and neuroinflammation in multiple brain regions at 1, 7, and 28 d post-exposure in the brains of DFP mice relative to VEH controls. Deficits in locomotor and home-cage behavior were observed in DFP mice at 28 d post-exposure. These findings demonstrate that this mouse model replicates many of the outcomes observed in rats and humans acutely intoxicated with OPs, suggesting the feasibility of using this model for mechanistic studies and therapeutic screening.

Rapid and robust sensing of nerve agent (NA) threats is necessary for real-time field detection to facilitate timely countermeasures. Unlike conventional phosphotriesterases employed for biocatalytic NA detection, this work describes the use of a new, green, thermally stable, and biocompatible zirconium metal-organic framework (Zr-MOF) catalyst, MIP-202(Zr). The biomimetic Zr-MOF-based catalytic NA recognition layer was coupled with a solid-contact fluoride ion-selective electrode (F-ISE) transducer, for potentiometric detection of diisopropylfluorophosphate (DFP), a F-containing G-type NA simulant. Catalytic DFP degradation by MIP-202(Zr) was evaluated and compared to the established UiO-66-NH2 catalyst. The efficient catalytic DFP degradation with MIP-202(Zr) at near-neutral pH was validated by 31P NMR and FT-IR spectroscopy and potentiometric F-ISE and pH-ISE measurements. Activation of MIP-202(Zr) using Soxhlet extraction improved the DFP conversion rate and afforded a 2.64-fold improvement in total percent conversion over UiO-66-NH2. The exceptional thermal and storage stability of the MIP-202/F-ISE sensor paves the way toward remote/wearable field detection of G-type NAs in real-world environments. Overall, the green, sustainable, highly scalable, and biocompatible nature of MIP-202(Zr) suggests the unexploited scope of such MOF catalysts for on-body sensing applications toward rapid on-site detection and detoxification of NA threats.

TiO2 and ZrO2 nanomaterials were successfully synthesized by sol gel method. Samples were characterized by X-ray difraction (XRD), Fourier-transform infrared spectroscopy (FTIR), N2 adsorption–desorption, Scanning electron microscopy (SEM), Transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS), SEM images and TEM images of TiO2 and ZrO2 samples showed the particle size of 10–20 nm. The results have revealed highly porous structure of ZrO2 and TiO2 nanomaterials with specific surface area of 116 m2g-1 and 125 m2g-1, respectively. The TiO2 and ZrO2 materials were used as the degradation of dimethyl 4-nitrophenyl phosphate (DMNP) chemical warfare agent emulator. The ZrO2 nanomaterial exhibited highly catalytic performance of DMNP degradation and the conversion reached to the value of 90.64 %, after 120 min of reaction.

Gulf War Illness (GWI), a disorder suffered by approximately 200,000 veterans of the first Gulf War, was caused by exposure to low-level organophosphate pesticides and nerve agents in combination with battlefield stress. To elucidate the mechanistic basis of the brain-related symptoms of GWI, human-induced pluripotent stem cells (hiPSCs) derived from veterans with or without GWI were differentiated into forebrain glutamatergic neurons and then exposed to a Gulf War (GW) relevant toxicant regimen consisting of a sarin analog and cortisol, a human stress hormone. Elevated levels of total and phosphorylated tau, reduced microtubule acetylation, altered mitochondrial dynamics/transport, and decreased neuronal activity were observed in neurons exposed to the toxicant regimen. Some of the data are consistent with the possibility that some veterans may have been predisposed to acquire GWI. Wistar rats exposed to a similar toxicant regimen showed a mild learning and memory deficit, as well as cell loss and tau pathology selectively in the CA3 region of the hippocampus. These cellular responses offer a mechanistic explanation for the memory loss suffered by veterans with GWI and provide a cell-based model for screening drugs and developing personalized therapies for these veterans.

The bis(2-chloroethyl) sulfide, commonly named sulfur mustard, as a vesicant agent and the tabun, sarin, soman, and venomous X as organophosphorus nerve agents are the most notorious, used, and threatening chemical warfare agents which contamination by them make serious health problems. The most efficient method for sulfur mustard detoxification is its selective oxidation to its corresponding sulfoxide, which is a nontoxic product. While for organophosphorus nerve agents, the best strategy is the hydrolysis of their P–X bond. Various mono-functional catalysts have been introducing regarding these methods. In other words, they are only able to selective oxidation of sulfur mustard or hydrolysis of organophosphorus nerve agents or their simulants. However, due to the unpredictable use of these chemical warfare agents, for human and environmental safety, there is a need for dual-functional catalysts capable of both the selective oxidation of sulfur mustard and hydrolysis of organophosphorus agents. In this regard, the reported dual-functional catalysts for oxidation of sulfur mustard and hydrolysis of organophosphorus agents, or their simulants, are reviewed here. These catalysts are mainly polyoxometalates and minorly metal-organic frameworks based catalysts.

The review considers and summarizes separation and preconcentration methods used in the determination of toxicants of the 1st hazard class, namely, organophosphorus nerve agents (a group of Vx isomers, sarin, cyclosarin, soman, and tabun) and blister agents (sulfur mustard).

For years, organophosphorus poisoning has been a major concern of health problems throughout the world. An estimated 200,000 acute pesticide poisoning deaths occur each year, many in developing countries. Apart from the agricultural pesticide poisoning, terrorists have used these organophosphorus compounds to attack civilian populations in some countries. Recent misuses of sarin in the Syrian conflict had been reported in 2018. Since the 1950s, the therapy to overcome this health problem is to utilize a reactivator to reactivate the inhibited acetylcholinesterase by these organophosphorus compounds. However, many questions remain unanswered regarding the efficacy and toxicity of this reactivator. Pralidoxime, MMB-4, TMB-4, obidoxime, and HI-6 are the examples of the established oximes, yet they are of insufficient effectiveness in some poisonings and only a limited spectrum of the different nerve agents and pesticides are being covered. Alternatively, an option in the treatment of organophosphorus poisoning that has been explored is through the use of enzyme therapy. Organophosphorus hydrolases are a group of enzymes that look promising for detoxifying organophosphorus compounds and have recently gained much interest. These enzymes have demonstrated remarkable protective and antidotal value against some different organophosphorus compounds in vivo in animal models. Apart from that, enzyme treatments have also been applied for decontamination purposes. In this review, the restrictions and obstacles in the therapeutic development of oximes, along with the new strategies to overcome the problems, are discussed. The emerging interest in enzyme treatment with its advantages and disadvantages is described as well.

Nerve agents are tetrahedral organophosphorus compounds (OPs) that were developed in the last century to irreversibly inhibit acetylcholinesterase (AChE) and therefore impede neurological signaling in living organisms. Exposure to OPs leads to a rapid development of symptoms from excessive salivation, nasal congestion and chest pain to convulsion and asphyxiation which if left untreated may lead to death. These potent toxins are prepared on a large scale from inexpensive staring materials, making it feasible for terrorist groups or states to use them against military and civilians. The existing antidotes provide limited protection and are difficult to apply to a large number of affected individuals. While new prophylactics are currently being developed, there is still need for therapeutics capable of both preventing and reversing the effects of OP poisoning. In this review, we describe how the science of molecular recognition can expand the pallet of tools for rapid and safe sequestration of nerve agents.

Nerve agents pose a real threat to both the military and civil populations, but the current treatment of the poisoning is unsatisfactory. Thus, we studied the efficacy of prophylactic use of memantine alone or in combination with clinically used reversible acetylcholinesterase inhibitors (pyridostigmine, donepezil, rivastigmine) against soman. In addition, we tested their influence on post-exposure therapy consisting of atropine and asoxime. Pyridostigmine alone failed to decrease the acute toxicity of soman. But all clinically used acetylcholinesterase inhibitors administered alone reduced the acute toxicity, with donepezil showing the best efficacy. The combination of memantine with reversible acetylcholinesterase inhibitors attenuated soman acute toxicity significantly. The pretreatment administered alone or in combinations influenced the efficacy of post-exposure treatment in a similar fashion: (i) pyridostigmine or memantine alone did not affect the antidotal treatment, (ii) centrally acting reversible acetylcholinesterase inhibitors alone increased the antidotal treatment slightly, (iii) combination of memantine with reversible acetylcholinesterase inhibitors increased the antidotal treatment more markedly. In conclusion, memantine alone failed to decrease the acute toxicity of soman or increase post-exposure antidotal treatment efficacy. The combination of memantine with donepezil significantly increased post-exposure effectiveness (together 5.12, pretreatment alone 1.72). Both drugs, when applied together, mitigate soman toxicity and boost post-exposure treatment.

Organophosphorus (OP) cholinesterase inhibitors, which include insecticides and chemical warfare nerve agents, are very potent neurotoxicants. Given that the actual treatment has several limitations, the present study provides a general method, called the zebrafish-OP-antidote test (ZOAT), and basic scientific data, to identify new antidotes that are more effective than the reference pyridinium oximes after acute OP poisoning. The reactivation capacity of a chemical compound can be measured using in vivo and ex vivo acetylcholinesterase (AChE) assays. We demonstrated that it is possible to differentiate between chemical compound protective efficacies in the central and peripheral nervous system via the visual motor response and electric field pulse motor response tests, respectively. Moreover, the ability to cross the brain-blood barrier can be estimated in a physiological context by combining an AChE assay on the head and trunk-tail fractions and the cellular and tissue localization of AChE activity in the whole-mount animal. ZOAT is an innovative method suitable for the screening and rapid identification of chemicals and mixtures used as antidote for OP poisoning. The method will make it easier to identify more effective medical countermeasures for chemical threat agents, including combinatorial therapies.

Prolonged seizures are a hallmark feature of intoxication with anticholinesterase nerve agents such as soman. While benzodiazepine drugs are typically used to control these seizures, studies in both rats and guinea pigs have shown that potent, centrally acting anticholinergic drugs such as scopolamine can also terminate such seizures. The present study was performed to determine if scopolamine could produce similar anticonvulsant effects in a nonhuman primate model of soman intoxication. Adult male African green monkeys, implanted with telemetry devices to record cortical electroencephalographic activity, were pretreated with pyridostigmine (0.02 mg/kg, intramuscularly [im]) and 40 min later challenged with 15 µg/kg (im) of the nerve agent soman. One min after soman exposure the animals were treated with atropine (0.4 mg/kg, im) and the oxime 2-PAM (25.7 mg/kg, im). One min after the start of seizure activity the animals were administered scopolamine (0.01-0.1 mg/kg, im), using an up-down dosing design over successive animals. Scopolamine was highly effective in stopping soman-induced seizures with an ED

Citrate reduction of gold (III) chloride trihydrate (HAuCl4) is commonly used method to synthesise citrate-capped gold nanoparticles (cit-AuNPs). In this study, the sequence of reagents addition was modified (“inverse” method) to synthesise smaller size of cit-AuNPs than the standard Turkevich method (“direct” method). Ultraviolet-visible spectroscopy (UV-vis) and field emission transmission electron microscopy (FETEM) confirmed the formation of cit-AuNPs. The cit-AuNPs synthesized using “inverse” method are smaller in size (14.0 ± 3.03 nm) with uniform spherical shape compared to “direct” method (23.5 ± 7.52 nm). Smaller particles size of cit-AuNPs provide higher efficiency and sensitivity for detection of methylphosphonic acid (MPA) via colorimetric incorporated with image processing with a linear range from 2.5 to 12.5 mM and a low detection limit of 6.28 mM at shorter detection period (24 to 30 s).

This paper reports a novel optical chemical sensing system for selective detection of diisopropylfluorophosphate (DFP), a simulant of fluorine-containing nerve agents (Sarin and Soman). Contrary to the reported methods involving only single sensing probe, this sensing system is comprised of two molecular sensing probes (1 and 2) having intrinsic affinities for reactive subunits of DFP (electrophilic phosphorus and fluoride ion). On exposure to DFP, two molecular probes react in tandem with electrophilic phosphorus and fluoride ion (by-product of the initial phosphorylation reaction) to induce a unique modulation in the optical properties of the sensing system which leads to selective detection of DFP in solution as interferents like phosphorus-containing compounds, acids, and anions were unable to induce similar optical modulation due to lack of both electrophilic phosphorus and fluorine in the same molecule. Calibration curve between the amount of DFP added and the absorption intensity revealed the colorimetric detection limit of the system to be 4.50 μM which was further lowered to 2.22 μM by making use of a self-immolative fluoride sensing probe 5.

Benzodiazepines are the primary treatment option for organophosphate (OP)-induced status epilepticus (SE), but these antiseizure drugs (ASDs) lose efficacy as treatment is delayed. In the event of a mass civilian or military exposure, significant treatment delays are likely. New ASDs that combat benzodiazepine-resistant, OP-induced SE are critically needed, particularly if they can be efficacious after a long treatment delay. This study evaluated the efficacy of the Kv7 channel modulator, retigabine, as a novel therapy for OP-induced SE. Adult, male rats were exposed to soman or diisopropyl fluorophosphate (DFP) to elicit SE and monitored by electroencephalogram (EEG) recording. Retigabine was administered alone or adjunctive to midazolam (MDZ) at delays of 20- or 40-min in the soman model, and 60-min in the DFP model. Following EEG recordings, rats were euthanized and brain tissue was collected for Fluoro-Jade B (FJB) staining to quantify neuronal death. In the DFP model, MDZ + 15 mg/kg retigabine suppressed seizure activity and was neuroprotective. In the soman model, MDZ + 30 mg/kg retigabine suppressed seizures at 20- and 40-min delays. Without MDZ, 15 mg/kg retigabine provided partial antiseizure and neuroprotectant efficacy in the DFP model, while 30 mg/kg without MDZ failed to attenuate soman-induced SE. At 60 mg/kg, retigabine without MDZ strongly reduced seizure activity and neuronal degeneration against soman-induce SE. This study demonstrates the antiseizure and neuroprotective efficacy of retigabine against OP-induced SE. Our data suggest retigabine could be a useful adjunct to standard-of-care and has potential for use in the absence of MDZ.

Following percutaneous exposure to the nerve agent VX, the remaining intact agent within the skin after decontamination is of great concern. Consequently, this leads to prolonged agent release to the blood circulation resulting in sustained intoxication, which may complicate the medical management. The decontamination procedure used should therefore possess the ability for agent removal both on and within the skin. The efficacy of three decontamination procedures was evaluated by measuring VX and the primary degradation product ethyl methyl phosphonic acid (EMPA) penetrated through human skin and the amount remaining within the skin.Decontamination was initiated 5 min post-exposure to VX on human dermatomed skin. Experiments were conducted using anIn control experiments without decontamination, higher amounts of VX were recovered in the deeper layers of skin compared to EMPA, which was primarily located in theEfficient skin decontamination of VX requires skin decontaminants reaching deeper layers of the skin, and that both absorption and degradation properties are important. In addition, the "wash-in" effect by using soapy water may enhance VX release to the blood circulation.

Metal-organic frameworks (MOFs) have shown promising properties for removal of chemical warfare agents, in particular for material decontamination and functionalized fabrics. The MOF-properties could also be beneficial for skin decontamination, especially when exposed to highly toxic and low volatile nerve agents. In such exposures, efficient decontamination is crucial for adequate medical management. In the present study, seven zirconium-based MOFs were evaluated for their ability to degrade VX and subsequently tested in vitro for decontamination of VX on human dermatomed skin. Of the MOFs evaluated, MOF-808 showed the greatest ability to degrade VX in an alkaline buffer with complete degradation of VX within 5 min. PCN-777, Zr-NDC and NU-1000 displayed degradation half-lives of approximately 10 min. When including MOF-808 in a skin friendly carrier with slightly acidic pH, a decreased agent degradation rate was observed, requiring over 24 h to reach complete degradation. In skin decontamination experiments, MOF-808 enhanced the efficacy compared to the carrier alone, essentially by improved agent absorption. Adding MOF-808 to Reactive Skin Decontamination Lotion (RSDL) did not improve the high effectiveness of RSDL alone. The present study showed that including MOF in skin decontamination lotions could be beneficial. Further studies should include optimizing the particulates and formulations.

A number of recent terrorist attacks make it clear that rapid response, high sensitivity and stability are essential in the development of chemical sensors for the detection of chemical warfare agents. Nerve agent sarin [2-(fluoro-methyl-phosphoryl) oxypropane] is an organophosphate (OP) compound that is recognized as one of the most toxic chemical warfare agents. Considering sarin’s high toxicity, being odorless and colorless, dimethyl methylphosphonate (DMMP) is widely used as its simulant in the laboratory because of its similar chemical structure and much lower toxicity. Thus, this review serves to introduce the development of a variety of fabricated chemical sensors as potential sensing materials for the detection of DMMP in recent years. Furthermore, the research and application of carbon anotubes in DMMP polymer sensors, their sensitivity and limitation are highlighted. For sorption-based sensors, active materials play crucial roles in improving the integral performances of sensors. The novel active materials providing hydrogen-bonds between the polymers and carbon nanotubes are the main focus in this review.

The recent use of organophosphate nerve agents in Syria, Malaysia, Russia, and the United Kingdom has reinforced the potential threat of their intentional release. These agents act through their ability to inhibit human acetylcholinesterase (hAChE; E.C. 3.1.1.7), an enzyme vital for survival. The toxicity of hAChE inhibition via G-series nerve agents has been demonstrated to vary widely depending on the G-agent used. To gain insight into this issue, the structures of hAChE inhibited by tabun, sarin, cyclosarin, soman, and GP were obtained along with the inhibition kinetics for these agents. Through this information, the role of hAChE active site plasticity in agent selectivity is revealed. With reports indicating that the efficacy of reactivators can vary based on the nerve agent inhibiting hAChE, human recombinatorially expressed hAChE was utilized to define these variations for HI-6 among various G-agents. To identify the structural underpinnings of this phenomenon, the structures of tabun, sarin, and soman-inhibited hAChE in complex with HI-6 were determined. This revealed how the presence of G-agent adducts impacts reactivator access and placement within the active site. These insights will contribute toward a path of next-generation reactivators and an improved understanding of the innate issues with the current reactivators.

VX is a representative nerve agent and its rapid detoxification relays on the development of catalysts and understanding of the mechanism on an atomic level. Herein, we report that a Lindqvist-type [Nb6O19]8− (Nb6) can effectively catalyze the detoxification of VX simulant, OSDEMP. Within 5 min OSDEMP can be completely converted to the minimally toxic product in the presence of H2O2. Various experimental evidences: (1) negligible conversion of DMNP (an organophosphorus ester without S center); (2) effect of solvent polarity; (3) 18O-labeled experiment confirm that the detoxification of OSDEMP by Nb6 follows an oxidation pathway. Further experimental and theoretical studies (e.g. spectroscopic analysis, control experiments, kinetic studies, and DFT calculations, etc.) reveal that Nb(ƞ1-OOH) hexaniobate is the dominant active species and both the formation of Nb(ƞ1-OOH) hexaniobate species and oxygen transfer process are rate-determining steps. The proposed mechanism can also be applied to the catalytic oxidation of sulfur mustard simulant.

In the realm of supramolecular chemistry, the development in synthetic receptors for harmful analytes has attracted substantial attention in recent decades due to the fact that a huge number of che...

Graphical abstract, Highlights • The median lethal dose of soman (GD) was estimated in adult male Göttingen minipigs. • GD exposure induces cholinesterase inhibition and behavioral seizure in minipigs. • GD induces neurodegeneration in visual cortex and lateral geniculate nucleus. • Prolonged seizure is associated with widespread microglial activation and cell death. • The minipig may be a useful alternative large animal model to the non-human primate., Animal models are essential for evaluating the toxicity of chemical warfare nerve agents (CWNAs) to extrapolate to human risk and are necessary to evaluate the efficacy of medical countermeasures. The Göttingen minipig is increasingly used for toxicological studies because it has anatomical and physiological characteristics that are similar to those of humans. Our objective was to determine whether the minipig would be a useful large animal model to evaluate the toxic effects of soman (GD). We determined the intramuscular (IM) median lethal dose (LD50) of GD in adult male Göttingen minipigs using an up-and-down dosing method. In addition to lethality estimates, we characterized the observable signs of toxicity, blood and tissue cholinesterase (ChE) activity and brain pathology following GD exposure. The 24 h LD50 of GD was estimated to be 4.7 μg/kg, with 95 % confidence limits of 3.6 and 6.3 μg/kg. As anticipated, GD inhibited ChE activity in blood and several tissues. Neurohistopathological analysis showed neurodegeneration and neuroinflammation in survivors exposed to 4.7 μg/kg of GD, including in the primary visual cortex and various thalamic nuclei. These findings suggest that the minipig will be a useful large animal model for assessing drugs to mitigate neuropathological effects of exposure to CWNAs.

Visual monitoring of the degradation of nerve agent simulants based on the switchable fluorescence of UiO-66-NH2 was developed. In the hydrolysis, the decomposition products perturbed the linker-to-cluster charge transfer and stimulated the fluorescence recovery. Moreover, a “soft” solid-state platform utilizing agarose hydrogels was proposed to visualize the degradation of gaseous simulants without bulk water.

A luminescent bis-porphyrin-salen-UO2 complex, showing a significant fluorescence light-up response upon reacting with DMMP (a simulant of nerve agents), is reported. The fluorescence change of this complex by excitation at 365 nm can be clearly observed with the naked eye, and this complex was successfully employed to construct a test paper to detect nerve agents.

The potential threat that has originated from chemical warfare agents (CWAs) has promoted the development of advanced materials to enhance the protection of civilian and military personnel. Zr-based metal–organic frameworks (Zr-MOFs) have recently been demonstrated as excellent catalysts for decomposing CWAs, but challenges of integrating the microcrystalline powders of Zr-MOFs into monoliths still remain. Herein, we report hierarchically porous monolithic UiO-66-X xerogels for the destruction of CWAs. We found that the UiO-66-NH2 xerogel with a larger pore size and a higher surface area than the UiO-66-NH2 powder possessed better degradability of 2-chloroethyl ethyl sulfide (2-CEES), which is a sulfur mustard simulant. These UiO-66-X xerogels exhibit outstanding performance for decomposing CWAs. The half-lives of vesicant agent sulfur mustard (HD) and nerve agent O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX) are as short as 14.4 min and 1.5 min, respectively. This work is, to the best of our knowledge, the first report on macroscopic monolithic UiO-66-X xerogels for ultrafast decomposition of CWAs.

Development of an efficient catalyst for degradation of organophosphorus toxicants is highly desirable. Herein, an MIL-101(Cr)LZn catalyst was fabricated by incorporating polypyridine zinc complexes into a MOF to achieve the spatial isolation of active sites. Compared with a terpyridine zinc complex without an MIL-101 support, this catalyst was highly active for detoxification of diethyl-4-nitrophenylphosphate.

Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable in vitro reactivation also pointed by the in silico studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.

Highlights • Evidence of poisoning with organophosphorus (OP) nerve agents requires biomedical verification. • OP nerve agents undergo common biotransformation pathways producing valuable biomarkers. • Internationally accepted methods target remaining poison, hydrolysis products and protein-adducts. • Mass spectrometry-based methods provide optimum selectivity and sensitivity for identification. • Methods, strategies, current proceedings, quality criteria and real cases of poisoning are presented., Intoxication by organophosphorus (OP) poisons, like nerve agents and pesticides, is characterized by the life-threatening inhibition of acetylcholinesterase (AChE) caused by covalent reaction with the serine residue of the active site of the enzyme (phosphylation). Similar reactions occur with butyrylcholinesterase (BChE) and serum albumin present in blood as dissolved proteins. For forensic purposes, products (adducts) with the latter proteins are highly valuable long-lived biomarkers of exposure to OP agents that are accessible by diverse mass spectrometric procedures. In addition, the evidence of poison incorporation might also succeed by the detection of remaining traces of the agent itself, but more likely its hydrolysis and/or enzymatic degradation products. These relatively short-lived molecules are distributed in blood and tissue, and excreted via urine. This review presents the mass spectrometry-based methods targeting the different groups of biomarkers in biological samples, which are already internationally accepted by the Organisation for the Prohibition of Chemical Weapons (OPCW), introduces novel approaches in the field of biomedical verification, and outlines the strict quality criteria that must be fulfilled for unambiguous forensic analysis.

The syntheses and crystal structures of a [15]paracyclophenone and its two fluorenone-containing derivatives I and II are reported. The nerve agent mimics binding behaviors with 2 and I driven by the ‘non-traditional’ aryl-CH hydrogen bonding interactions are demonstrated in the solid state and supported by DFT calculations. The affinity of compound I towards the real nerve agents via this binding mode is also predicted by the computational method.

In this study, a carboxymethyldextran chip based sensor system is developed that selectively recognizes and binds nerve agent molecules used in chemical weapons. Nerve agents fall under the group of organophosphorus compounds and irreversibly inhibit the acetylcholinesterase enzyme (AChE). In this study, parathion was used as an organophosphorus compound. The effect of the parathion molecule on enzyme inhibition is similar to nerve agents. The first step to be applied before CMD (Carboxymethyldextran) chip surface enzyme immobilization is the surface activation. After the surface activation was completed, AChE enzyme solution was passed over the chip surface for 40 minutes. In this way, enzyme immobilization was performed on the chip surface and a surface selective to the parathion molecule was obtained. Analysis was performed for parathion samples in different concentrations in the range of 3.43x10-8-6.86x10-4 mol/L. When the analysis results were transferred to the calibration graph, a graphic close to the linear was obtained. The working range of the chip surface developed as a result of the analyzes was calculated as 3.43x10-8 - 6.86x10-4, the limit of detection (LOD) value was 3.79x10-8 and the limit of quantification (LOQ) value was 6.16x10-8. These results show that samples containing parathion at very low concentrations can be analyzed using the method we have developed.

Despite a recent dramatically increased risk of using chemical warfare agents in chemical attacks and assassinations, fundamental interactions of toxic chemicals with other materials are poorly understood, and micromechanisms of their chemical degradation are yet to be established. This represents an outstanding challenge in both fundamental science and practical applications in combat against chemical weapons. One of the most versatile and multifunctional oxides, TiO2, has been suggested as a promising material to quickly adsorb and effectively destroy toxins. In this paper, we explore how sarin (also known as GB) adsorbs and decomposes on dry nanoparticles of TiO2 anatase and rutile phases. We found that both anatase and rutile readily adsorb sarin gas molecules because of a strong electrostatic attraction between the phosphoryl oxygen and surface titanium atoms. The sarin decomposition most likely proceeds via a propene elimination; however, the reaction is exothermic on the rutile (110) surface and endothermic on the anatase (101) surface. High energy barriers suggest that sarin would hardly decompose on pristine dry surfaces of TiO2, and degradation reactions can be triggered by defects or contaminants under realistic operational conditions.

Because organophosphate-based nerve agents still pose a significant threat to society, development of an efficient catalyst for detoxification is highly desirable and yet challenging. In this issue of Chem Catalysis, Farha et al. report a Zr-MOF/hydrogel composite for rapid hydrolysis of nerve agents and achieve the highest efficiency to date under practical conditions.

We have adopted the concept of bispecific antibodies, which can simultaneously block or cross-link two different biomolecular targets, to create bispecific enzymes by exploiting the homodimeric quaternary structure of bacterial phosphotriesterases (PTEs). The PTEs from Brevundimonas diminuta and Agrobacterium radiobacter, whose engineered variants can efficiently hydrolyze organophosphorus (OP) nerve agents and pesticides, respectively, have attracted considerable interest for the treatment of the corresponding intoxications. OP nerve agents and pesticides still pose a severe toxicological threat in military conflicts, including acts of terrorism, as well as in agriculture, leading to >100000 deaths per year. In principle, engineered conventional homodimeric PTEs may provoke hydrolytic inactivation of individual OPs in vivo, and their application as catalytic bioscavengers via administration into the bloodstream has been proposed. However, their narrow substrate specificity would necessitate therapeutic application of a set or mixture of different enzymes, which complicates biopharmaceutical development. We succeeded in combining subunits from both enzymes and to stabilize their heterodimerization by rationally designing electrostatic steering mutations, thus breaking the natural C2 symmetry. The resulting bispecific enzyme from two PTEs with different bacterial origin exhibits an ultrabroad OP substrate profile and allows the efficient detoxification of both nerve agents and pesticides. Our approach of combining two active sites with distinct substrate specificities within one artificial dimeric biocatalyst-retaining the size and general properties of the original enzyme without utilizing protein mixtures or much larger fusion proteins-not only should facilitate biological drug development but also may be applicable to oligomeric enzymes with other catalytic activities.

As social media becomes increasingly ubiquitous, many events are recorded and released on social media platforms, including chemical weapon attacks. We develop an objective tool in order to evaluate brief and unstructured social media videos for analysing sarin exposure from a civilian medical pathology perspective. We developed and validated this new questionnaire using a standardized procedure that includes content domain specification, item pool generation, content validity evaluation, a pilot study, and assessment of reliability and validity. In total, 51 sarin attacks and 48 matched videos were analysed. Cronbach’s α for all 20 items was 0.75, which indicates adequate internal reliability. The test–retest reliability was 0.96, which indicates good internal reliability. The inter-observer intraclass correlation coefficient was 0.97. After verifying sampling adequacy with the Kaiser–Meyer–Olkin measure and the factorability of the items with Barlett’s test of sphericity, a factor analysis was performed. According to the principal axis factoring, a six-factor solution explained 51.86% of the total variance. The receiver-operating characteristic curve analysis showed that the Video Score Questionnaire has a sensitivity of 0.817, a specificity of 0.478, and an efficiency of 65.3. Therefore, the Video Score Questionnaire is reliable and valid for evaluating sarin attacks from brief and unstructured social media videos. Key points Chemical weapons are still used as a method of warfare. Social media videos are an important source of information. We developed a validated scale which can analyse sarin exposure in short and unstructured videos.

Nerve agents and neurobiological weapons are among the most devastating and lethal of weapons. Acetylcholinesterase inhibitors act by increasing the amount of acetylcholine in the neuromuscular junction, resulting in flaccid paralysis. Tabun, VX, soman, and sarin are the major agents in this category. Exposure to nerve agents can be inhalational or through dermal contact. Neurotoxins may have peripheral and central effects on the nervous system. Atropine is an effective antidote to nerve agents. Neurobiological weapons entail using whole organisms or organism-synthesized toxins as agents. Some organisms that can be used as biological weapons include smallpox virus.

β-cyclodextrins (β-CDs) are able to trap and hydrolyze certain nerve agents such as sarin. Herein, we studied the host-guest interactions of sarin with β-CD by performing quantum mechanical (QM) calculations and molecular dynamics (MD) simulations. The calculated results indicated that the stable inclusion complex can be formed in both vacuum and water. Also, dynamic and structural parameters revealed that the intramolecular hydrogen bonds and van der Waals interactions effectively help to maintain the stability of the sarin structure within the β-CD cavity. More importantly, it was shown that how the interactions of host’ components with phosphorus and fluorine of sarin can help to hydrolysis and thus detoxify sarin.

In this paper, we propose a new strategy for the sensitive and specific detections of dimethyl methylphosphonate (DMMP), as a simulant of nerve agent Sarin. Our silicon nanowire based sensor is modified with carboxyphenylboronic acid (CPBA) to demonstrate great efficiency. The response time is less than 100 seconds to recognize the DMMP, which is a key ability for on-site monitoring. The sensor exhibits a good reversibility during the repeated measurements between DMMP vapor and air. The sensor still performs well after being exposed in high concentration of DMMP vapor with excellent recovery for 3 times. The sensor is demonstrated to have a linear behavior in detecting DMMP within the concentration of 13~65 ppm in gaseous phase with the limit of detection (LOD) of 100 ppb. It is expected that the proposed sensor enables the testing system accurate, rapid, sensitive and reversible for on-site detection of nerve agents in the future.

Therapeutic efficacy of antidotal treatment of acute poisoning by nerve agents is generally assessed by the evaluation of LD50 values of nerve agents over 24 h following poisoning without or with a...

Studies with acetylcholinesterase (AChE) inhibited by organophosphorus (OP) compounds with two chiral centers can serve as models or surrogates for understanding the rate, orientation, and postinhibitory mechanisms by the nerve agent soman that possesses dual phosphorus and carbon chiral centers. In the current approach, stereoisomers of O-methyl, [S-(succinic acid, diethyl ester), O-(4-nitrophenyl) phosphorothiolate (MSNPs) were synthesized, and the inhibition, reactivation, and aging mechanisms were studied with electric eel AChE (eeAChE) and recombinant mouse brain AChE (rmAChE). The MSNP RPRC isomer was the strongest inhibitor of both eeAChE and rmAChE at 8- and 24-fold greater potency, respectively, than the weakest SPSC isomer. eeAChE inhibited by the RPRC- or RPSC-MSNP isomer underwent spontaneous reactivation ∼10- to 20-fold faster than the enzyme inhibited by SPRC- and SPSC-MSNP, and only 4% spontaneous reactivation was observed from the SPRC-eeAChE adduct. Using 2-pyridine aldoxime methiodide (2-PAM) or trimedoxime (TMB-4), eeAChE inhibited by RPRC- or SPRC-MSNP reactivated up to 90% and 3- to 4-fold faster than eeAChE inhibited by the RPSC- or SPSC-MSNP isomer. Spontaneous reactivation rates for rmAChE were 1.5- to 10-fold higher following inhibition by RPSC- and SPSC-MSNPs than inhibition by either RC isomer, a trend opposite to that found for eeAChE. Oxime reactivation of rmAChE following inhibition by RPRC- and SPRC-MSNPs was 2.5- to 5-fold faster than inhibition by RPSC- or SPSC-MSNPs. Due to structural similarities, MSNPs that phosphylate AChE with the loss of the p-nitrophenoxy (PNP) group form identical, nonreactivatable adducts to those formed from SP-isomalathion; however, all the MSNP isomers inhibited AChE to form adducts that reactivated. Thus, MSNPs inactivate AChE via the ejection of either PNP or thiosuccinyl groups to form a combination of reactivatable and nonreactivatable adducts, and this differs from the mechanism of AChE inhibition by isomalathion.

Chemical warfare agents (CWAs), and in particular organophosphorus nerve agents, still pose a significant threat to society due to their continued use despite international bans. While nature has c...

Organophosphorus compounds, such as chemical warfare nerve agents and pesticides, are known to cause neurological damage. This study measured nerve agent-related neuropathology and determined whether quantitative T2 MRI could be used as a biomarker of neurodegeneration. Quantitative T2 MRI was performed using a 9.4 T MRI on rats prior to and following soman exposure. T2 images were taken at least 24 h prior, 1 h and 18–24 h after soman exposure. Rats were pre- and post-treated with HI-6 dimethanesulfonate and atropine methyl nitrate. A multicomponent T2 acquisition and analysis was performed. Brains were stained with Fluoro-Jade C to assess neurodegeneration. Rats exposed to soman developed behavioral expression of electrographic seizures. At 18–24 h after soman exposure, significant increases in T2, a possible marker of edema, were found in multiple regions. The largest changes were in the piriform cortex (before: 47.7 ± 1.4 ms; 18–24 h: 82.3 ± 13.4 ms). Fluoro-Jade C staining showed significant neurodegeneration 18–24 h post exposure. The piriform cortex had the strongest correlation between the change in relaxation rate and percent neurodegeneration (r = 0.96, p 2 relaxivity and histopathology supports the use of T2 as a marker of injury.